Cancer patients often experience life-threatening complications, such as cancer-associated thrombosis (CAT) and cancer-associated cachexia (CAC), contributing to a decline in their quality of life and prognosis. These complications also impose a substantial financial burden on healthcare systems [1].
CAT and CAC share a common feature of systemic inflammation, contributing to their pathogenesis. The prevalence and mechanisms underlying the potential connection between these two conditions remain largely unexplored, with no well-established molecular pathways identified yet. The percentage of patients affected by both CAT and CAC is currently unknown, and the biological processes driving these disorders are still not fully understood [2, 3].
To address these knowledge gaps, a review article conducted in 2022 examined scientific literature from the past 60 years, focusing on databases such as PubMed, Scopus, SciELO, MEDLINE and Web of Science. The study explored the association between cancer and either thrombosis or cachexia, aiming to shed light on the potential link and underlying mechanisms between CAT and CAC [4].
Cachexia
Cachexia is a chronic syndrome prevalent among patients with chronic illnesses, such as Crohn’s disease, AIDS and cancer. It involves persistent wasting of skeletal muscle mass, often accompanied by loss of adipose tissue mass, leading to partial disability despite attempts at nutritional support and physical therapy. Distinguishing cachexia from related conditions, such as sarcopenia, starvation, or malabsorption relies on factors, such as significant weight loss within a specified time frame, considering the patient’s BMI and skeletal muscle index. Dual-energy X-ray absorptiometry plays a crucial role in this differentiation [5].
Affecting over half of cancer patients, especially those in advanced disease stages, CAC significantly impacts the quality of life, response to anti-neoplastic therapy, and susceptibility to postoperative complications, contributing to shorter disease-free survival. Additionally, CAC can lead to cardiac muscle wasting, resulting in organ dysfunction and potential fatality [4].
Clinical risk factors influencing CAC include patient-related factors, such as advanced age, male gender and specific genetic markers, as well as various conditions, such as physical trauma, infections, endocrine abnormalities, kidney failure, chronic obstructive pulmonary disease and inflammatory bowel disease. The incidence of CAC varies based on tumor type and stage, with pancreatic carcinoma patients being the most affected. Cancer treatments, including chemotherapy, surgery, radiotherapy and cancer immunotherapy, contribute to CAC through the release of pro-cachectic molecules and the induction of a catabolic state [6].
CAC’s pathogenesis revolves around a combination of reduced food intake and abnormal metabolism, primarily driven by a pro-inflammatory state. This state triggers a neuroendocrine response leading to anorexia and metabolic derangement, ultimately causing the degeneration of muscle mass and adipose tissue. Pro-inflammatory cytokines like TNF-α, IL-1, IL-6, IL-8 and IFN-γ play critical roles in CAC development, triggered by both tumor-derived factors and host cells [4].
Thrombosis and cachexia
Thrombosis and cachexia frequently complicate the course of cancer, significantly affecting patient outcomes. Despite their substantial impact, the potential interplay between the two remains largely unexplored. Analysis of clinical and biological factors associated with CAT and CAC reveals shared underlying pathophysiological mechanisms [3]. Both CAT and CAC are increasingly prevalent, often manifesting during cancer diagnosis and progression, posing a threat to treatment efficacy. Patient-related factors, such as age, race, trauma and performance status, alongside comorbidities (including liver or kidney diseases and immune or pulmonary disorders), contribute to both conditions. Gender also plays a significant role, with distinct risk patterns observed. Tumor-related factors, particularly specific cancer types, are associated with a heightened risk of CAT and CAC, often linked to a chronic pro-inflammatory state. Furthermore, cancer treatments such as chemotherapy, surgery and radiotherapy can significantly contribute to the development of both conditions [4].
In terms of biological mechanisms, chronic inflammation, metabolic dysregulation and hormonal imbalances appear to be critical components linking CAT and CAC. Cytokines, such as TNF-α and IL-6, as well as monocytes/macrophages, play significant roles in both conditions, contributing to thrombotic events and muscle wasting [7, 4].
Metabolic syndrome, diabetes, insulin resistance, and hormonal disruptions further intertwine the pathophysiology of CAT and CAC with implications for thrombogenesis and tissue wasting. Monocytes and macrophages, playing critical roles in thrombosis and muscle wasting, contribute to the overall pathophysiology of both conditions, further emphasizing the complex interplay between inflammation and coagulation [4].
The role of various hormones, including sex hormones, thyroid hormones, and leptin, is crucial in understanding the connections between CAT and CAC. Disturbances in these hormonal systems may contribute to the development and progression of both conditions, highlighting the need for a comprehensive understanding of their impact on the intricate pathways involved [4].
The management of these complications demands a multidisciplinary approach, emphasizing regular assessments and the development of comprehensive risk assessment tools [4]. Although the potential association between the two conditions holds promise, further research is needed to elucidate their precise interactions and influences on each other [7].
Conclusion
In summary, the challenges posed by thrombosis and cachexia significantly impact the well-being and longevity of cancer patients. While the exact prevalence of both conditions occurring together remains unclear, shared risk factors suggest a potential relationship between CAT and CAC. Chronic inflammation, metabolic dysregulation, and hormonal imbalances appear to be crucial factors linking these complications. Understanding these shared pathways can aid in the development of predictive markers and therapies for both CAT and CAC [4].
However, the exact nature of the association between CAT and CAC remains uncertain. Further investigations are needed to clarify the factors influencing the prevalence of one condition over the other, enabling more effective screening and management strategies. If a positive association is confirmed, the development of combined screening methods and treatment approaches targeting both conditions, with a focus on anti-inflammatory and anti-coagulation therapies, could be beneficial. Moreover, enhancing the management of cachexia may help reduce the risk of thrombosis, given the association of cachexia with reduced mobility, a known risk factor for thrombosis [4].
In clinical practice, recognizing potential links between CAT and CAC is critical for improving prevention, diagnosis, and management strategies. Regular assessments for both conditions, alongside multidisciplinary approaches involving various healthcare professionals, are essential in addressing the complex challenges posed by these intertwined complications. Additionally, the development of robust risk assessment tools and comprehensive education for patients and caregivers are crucial components of effective management strategies [4].
Future research
Further research focused on unraveling the intricate connections between CAT and CAC is imperative to enhance our understanding of their shared pathophysiology. By uncovering the mechanisms underlying their relationship, we can potentially identify novel targets for therapeutic interventions, leading to improved outcomes and better quality of life for cancer patients grappling with these challenging complications.
References
- Stubbins R, Bernicker EH, Quigley EMM. Cancer cachexia: a multifactoral disease that needs a multimodal approach. Curr Opin Gastroenterol. 2020;36(2):141-146. doi:10.1097/MOG.0000000000000603
- Poulia KA, Sarantis P, Antoniadou D, et al. Pancreatic cancer and cachexia-metabolic mechanisms and novel insights. Nutrients. 2020;12(6):1543. doi:10.3390/nu12061543
- Bossi P, Delrio P, Mascheroni A, Zanetti M. The spectrum of malnutrition/cachexia/sarcopenia in oncology according to different cancer types and settings: a narrative review. Nutrients. 2021;13(6):1980. doi:10.3390/nu13061980
- Liz-Pimenta J, Tavares V, Neto BV, et al. Thrombosis and cachexia in cancer: Two partners in crime? Crit Rev Oncol Hematol. 2023;186:103989. doi:10.1016/j.critrevonc.2023.103989
- Peixoto da Silva S, Santos JMO, Costa E Silva MP, Gil da Costa RM, Medeiros R. Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia. J Cachexia Sarcopenia 2020;11(3):619-635. doi:10.1002/jcsm.12528
- Koppe L, Fouque D, Kalantar-Zadeh K. Kidney cachexia or protein-energy wasting in chronic kidney disease: facts and numbers. J Cachexia Sarcopenia Muscle. 2019;10(3):479-484. doi:10.1002/jcsm.12421
- Divella R, Gadaleta Caldarola G, Mazzocca A. Chronic inflammation in obesity and cancer cachexia. J Clin Med. 2022;11(8):2191. doi:10.3390/jcm11082191